1. Field of the Invention
The invention relates to a diffusion barrier layer for implantable devices or endoluminal prostheses. More particularly the invention relates to a coating disposed on an implantable device, one example of which includes a stent, for inhibiting the release rate of an active ingredient carried by the device.
2. Description of the Background
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion for remodeling of the vessel wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient""s vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the conduit after the balloon is deflated. Vasospasms and recoil of the vessel wall also threaten vessel closure. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, an expandable, intraluminal prosthesis, one example of which includes a stent, is implanted in the lumen to maintain the vascular patency.
Stents are used not only as a mechanical intervention but also as a vehicle for providing biological therapy. As a mechanical intervention, stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway. Typically stents are capable of being compressed, so that they can be inserted through small cavities via catheters, and then expanded to a larger diameter once they are at the desired location. Examples in the patent literature disclosing stents which have been successfully applied in PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor. Mechanical intervention via stents has reduced the rate of restenosis as compared to balloon angioplasty; but restenosis is still a significant clinical problem with rates ranging from 20-40%. When restenosis does occur in the stented segment, its treatment can be challenging, as clinical options are more limited as compared to lesions that were treated solely with a balloon.
Biological therapy can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results.
One proposed method for medicating stents disclosed seeding the stents with endothelial cells (Dichek, D. A. et al. Seeding of Intravascular Stents With Genetically Engineered Endothelial Cells; Circulation 1989; 80:1347-1353). Briefly, endothelial cells were seeded onto stainless steel stents and grown until the stents were covered. The cells were therefore able to be delivered to the vascular wall where they provided therapeutic proteins. Another proposed method of providing a therapeutic substance to the vascular wall included use of a heparin-coated metallic stent, whereby a heparin coating was ionically or covalently bonded to the stent. Significant disadvantages associated with the aforementioned method includes significant loss of the therapeutic substance from the body of the stent during delivery and expansion of the stent, and an absolute lack of control of the release rate of the proteins from the stent.
Another proposed method involved the use of a polymeric carrier coated onto the surface of a stent, as disclosed in U.S. Pat. No. 5,464,650 issued to Berg et al. Berg disclosed applying to a stent body a solution which included a specified solvent, a specified polymer dissolved in the solvent, and a therapeutic substance dispersed in the blend. The solvent was allowed to evaporate, leaving on the stent surface a coating of the polymer and the therapeutic substance impregnated in the polymer.
Depending on the physiological mechanism targeted, the therapeutic substance may be required to be released at an efficacious concentration for an extended duration of time. Increasing the quantity of the substance in the polymeric coating can lead to poor coating mechanical properties, inadequate coating adhesion, and overly fast rate of release. Increasing the quantity of the polymeric compound and producing a thicker coating can perturb the geometrical and mechanical functionality of the stent, as well as limit the procedure for which the sent can be used.
It is desirable to increase the residence time of a substance at the site of implantation, at a therapeutically useful concentration, without the need for the application of a thicker coating or increasing the quantity of the therapeutic substance.
In accordance with one aspect of the present invention, a coating for a prosthesis is provided that serves as a barrier layer. The coating contains particles. The coating can be made from a polymeric material, such as ethylene vinyl alcohol copolymer. The prosthesis can be, for example, a balloon-expandable stent, a self-expandable stent, or a graft. The prosthesis can include cavities containing an active ingredient for the release of the active ingredient when the stent is implanted. Alternatively, the prosthesis can include a reservoir coating carrying an active ingredient. The coating containing the particles acts as a rate reducing membrane for the release of the active ingredient. In accordance with another embodiment, a primer layer which serves as an adhesive tie between the surface of the prosthesis and the reservoir coating can be provided. The reservoir coating and the primer layer can be made from any suitable polymeric material such as ethylene vinyl alcohol copolymer.
In accordance with another aspect of the invention, a method of forming a coating supported by an implantable device, for example a stent, is provided. A first composition containing particles is applied to the implantable device to form a coating containing the particles. The coating containing the particles acts as a rate reducing membrane for the release of an active ingredient. The coating can be made from a polymeric material such as ethylene vinyl alcohol copolymer. In accordance with one embodiment, the implantable device includes cavities containing the active ingredient. In accordance with another embodiment, prior to the act of applying the first composition, a second composition containing the active ingredient is applied to the implantable device to form a reservoir coating. The reservoir coating can be a polymeric material such as ethylene vinyl alcohol copolymer. In accordance with another embodiment, a third composition can be applied to the surface of the device to form an intermediary tie layer between the device and the reservoir coating.
The particles can be made form any suitable organic or inorganic material. In one embodiment, the particles are made from metals, metal oxides, carbonaceous compounds, main group oxides, nitrides, carbides, calcium salts, or combinations thereof. Such materials, more particularly, can include rutile titanium oxide, anatase titanium dioxide, niobium oxide, tantalum oxide, zirconium oxide, iridium oxide, tungsten oxide, silica, alumina, gold, hafnium, platinum, iridium, palladium, tungsten, tantalum, niobium, zirconium, titanium, aluminum, chromium, lamp black, furnace black, carbon black, fumed carbon black, gas black, channel black, activated charcoal, diamond, titanium nitride, chromium nitride, zirconium nitride, tungsten carbide, silicon carbide, titanium carbide, hydroxyapatite, dahlite, brushite, tricalcium phosphate, calcium sulphate, calcium carbonate, silicides, barium titanate, strontium titanate.
In accordance with another embodiment the particles can be made from a polymeric material such as polymers of polyolefins, polyurethanes, cellulosics, polyesters, polyamides, poly(hexamethylene isophthalamide/terephthalamide), poly(ethylene terephthalate-co-p-oxybenzoate), poly(hydroxy amide ethers), polyacrylates, polyacrylonitrile, acrylonitrile/styrene copolymer, rubber-modified acrylonitrile/acrylate copolymer, poly(methyl methacrylate), liquid crystal polymers, poly(phenylene sulfide), polystyrenes, polycarbonates, poly(vinyl alcohols), poly(ethylene-vinyl alcohol), epoxies composed of bisphenol A based diepoxides with amine cure, aliphatic polyketones, polysulfones, poly(ester-sulfone), poly(urethane-sulfone), poly(carbonate-sulfone), poly(3-hydroxyoxetane), poly(amino ethers), gelatin, amylose, parylene-C, parylene-D, parylene-N, or combinations thereof.
Representative example of polyolefins include polyethylenes, poly (vinyl chloride), poly (vinylidene chloride), poly (vinyl fluoride), poly (vinylidene fluoride), poly (tetrafluoroethylene), poly (chlorotrifluoroethylene), or combinations thereof.
Representative examples of polyurethanes include polyurethanes having a glass transition temperature above physiologic temperature, or having a non-polar soft segment which includes hydrocarbons, silicones, fluorosilicones, or combinations thereof.
Representative examples of cellulosics includes cellulose acetate having a degree of substitution (DS) greater than about 0.8 or less than about 0.6, ethyl cellulose, cellulose nitrate, cellulose acetate butyrate, methyl cellulose, or combinations thereof.
Representative examples of polyesters include saturated or unsaturated polyesters, including poly (ethylene terephthalate), poly(ethylene 2,6-naphthalene dicarboxylate), poly (butylene terephthalate), or combinations thereof.
Representative examples of polyamides include crystalline or amorphous polyamides including nylon-6, nylon-6,6, nylon-6,9, nylon-6,10, aromatic nylon, or combinations thereof.